Comparison of Conformational Analyses of Naturally Occurring Flavonoid-O-Glycosides with Unnatural...

Many glycosylated natural products display biological activity and are deglycosylated by the metabolic processes of the body. Although unnatural CF₂-glycosides have been proposed as nonhydrolyzable analogues, CF₂-derivatives of natural products are exceedingly challenging to synthesize and few examples exist. These difluorinated molecules may have unique conformational behavior as a consequence of changing the glycosidic linkage. In this study, we performed conformational searches using MacroModel followed by molecular dynamics simulations to investigate the conformational behavior of the glycosidic bonds in flavonoid-O-glycosides and in corresponding CF₂-glycosylated derivatives. Compared to their O-glycosylated analogues, flavonoid-3-CF₂-glycosides and flavonoid-5-CF₂-glycosides showed conformational bias, whereas flavonoid-7-CF₂-glycosides showed more flexibility. Flavonoid-5-CF₂-glycosides were the least flexible compared to all others. Our results show that the site of the glycosylation and the substitution pattern on the flavonoid determine the conformational properties of these molecules. These two factors influence the steric destabilization and/or stereoelectronic stabilization which govern the conformational behavior of the flavonoid glycosides. Moreover, a docking study of quercitrin and its CF₂-analogue into murine ribosomal kinase RSK2 demonstrated the potential for flavonoid-CF₂-glycosides to retain a similar binding pose as the parent O-glycoside. These findings will assist in designing stable flavonoid-CF₂-glycosides for carbohydrate research.